Candida albicans is the most widespread fungal pathogen of humans and one of the most frequent hospital-acquired infections (Gudlaugsson, Clin. Infect. Dis. 37:1172-1177, 2003; Miller, Clin. Infect. Dis. 15:523-530, 2001; Pappas, Clin. Infect. Dis. 37:634-643, 2003). The estimated annual cost of treating nosocomial Candida infections exceeds $1 billion per year (Miller, supra; Pappas, supra). As an opportunistic pathogen, it is responsible for common clinical problems including, e.g., oral thrush and vaginitis, but can also lead to life-threatening systemic infections (candidiasis) in immunocompromised individuals (Fidel, Clin. Microbiol. Rev. 9:335-348, 1996), resulting in 30-50% mortality rates (Gudlaugsson, supra; Rangel-Frausto, Clin. Infect. Dis. 29:253-258, 1999). A contributing factor to these statistics is the ability of C. albicans to develop resistance to antifungal drugs (Cowen, Proc. Nat'l. Acad. Sci. U.S.A. 99:9284-9286, 2002). Moreover, most effective antifungal drugs also cause serious side effects, in many cases because of the significant homology between mammalian and fungal drug targets (Cowen, supra). With such complications, new strategies for combating fungal infections without toxicity to humans are a high medical priority.
Adhesion to surfaces is the first critical step in establishing a fungal infection. Candida cells with a planktonic “yeast” morphology initiate adhesion, and a subsequent transition from yeast to hyphal morphology contributes to invasion of the host tissue and formation of biofilms (Bendel, Crit. Care Med. 31:501-507, 2003; Saville, Eukaryot. Cell 2:1053-1060, 2003; Lo et al., Cell 90:939-949, 1997; Finkel, Nat. Rev. Microbiol. 9:109-118, 2010). Biofilm formation is a medically crucial step in pathogenesis, because biofilm-associated infections normally do not respond to conventional treatment, and because systemic candidiasis usually results from biofilms originating on intravascular devices and catheters (Douglas, Trends Microbiol. 11:30-36, 2003; Blankenship, Curr. Opin. Microbiol. 9:588-594, 2006; Nobile et al., Eukaryot. Cell 5:1604-1610, 2006). Candida cells released from these devices can be disseminated into the bloodstream, where fungal organisms adhere to endothelial surfaces and then penetrate blood vessels, spreading infection to multiple organs. Because biofilm-associated medical devices are resistant to treatment with existing therapeutics, it is often necessary to remove the devices in order to completely treat infections (Bauters, J. Clin. Microbiol. 40:1838-1839, 2002).
There still exists a need for effective antifungal agents that can be used to combat fungal infections without toxicity to humans.